CAR T cell therapy in AML could advance through the identification of 13 promising antigen targets, according to a comprehensive review that evaluated 63 acute myeloid leukaemia associated antigens using a structured scoring framework designed to support next generation therapeutic development.
Challenges Facing CAR T Cell Therapy in AML
Acute myeloid leukaemia (AML) remains an aggressive haematological malignancy associated with limited treatment options and poor long-term outcomes. A major obstacle to achieving durable remission is the persistence of leukaemic stem cells, a chemotherapy resistant population that can drive disease relapse.
Although CAR T cell therapy has transformed outcomes in several B cell malignancies, progress in AML has been slower. One of the principal challenges is the lack of highly specific target antigens. Many potential targets are shared between malignant cells and normal haematopoietic stem cells or mature blood cells, creating a risk of on target off tumour toxicity and treatment related myeloablation.
Early clinical studies targeting antigens such as CD123, CD33, and CLL 1 have produced limited durable complete remissions and, in some cases, substantial toxicity. These findings have highlighted the need for more selective targets capable of distinguishing AML cells from healthy tissues.
Systematic Assessment of AML Antigens
To address this challenge, researchers systematically reviewed 63 AML associated antigens for which CAR constructs have been reported. Each antigen was assessed using five predefined criteria: homogeneous expression across patients with AML; uniform expression within individual patients; presence on leukaemic stem cells; absence on normal haematopoietic stem cells; and no or acceptable expression on mature blood cells.
Using a 20 point scoring system, the investigators identified 13 antigens that emerged as the most promising candidates for future CAR T cell therapy in AML development.
The prioritised targets were ADGRE2, SIGLEC 6, IL1RAP, MUC1, CCR1, CD155, CD70, LILRB4, GRP78, CD37, ITGB2, TIM 3, and mesothelin.
Framework for Future CAR T Cell Development
The review examined both the strengths and limitations of each target and outlined potential strategies to reduce treatment associated risks. Importantly, several of the prioritised antigens may offer improved selectivity compared with targets currently under investigation.
With no CAR T cell therapy currently approved for AML, the authors propose that this prioritised antigen landscape may help guide the rational design of future therapies. By focusing on targets with favourable expression patterns on leukaemic stem cells and reduced overlap with healthy blood forming tissues, researchers may be better positioned to develop safer and more effective CAR T cell approaches for this difficult to treat disease.
Reference
Oers FV et al. The search for safe and effective CAR-T targets in AML. Blood Cancer Journal. 2026; https://doi.org/10.1038/s41408-026-01544-5.
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